Obesity and diabetes are predicted to reach epidemic proportions throughout the world in the next 20 years and current treatments do not restore normal insulin sensitivity or glucose homeostasis, therein resulting in debilitating diabetic complications and premature death.
Gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1(7-36)amide (truncated GLP-1; tGLP-1) are two important insulin-releasing hormones secreted from endocrine cells in the intestinal tract in response to feeding. Together with autonomic nerves they play a vital supporting role to the pancreatic islets in the control of blood glucose homeostasis and nutrient metabolism.
GIP is released from intestinal endocrine K-cells into the bloodstream following ingestion of carbohydrate, protein and particularly fat (Meier, J. J. et al., 2002, Regul. Pept. 107:1-13). GIP was initially discovered through its ability to inhibit gastric acid secretion (Brown, J. C. et al. 1969, Can. J. Physiol. Pharmacol. 47:113-114) but its major physiological role is now generally believed to be that of an incretin hormone that targets pancreatic islets to enhance insulin secretion and help reduce postprandial hyperglycemia (Creutzfeldt, W., 2001, Exp. Clin. Endocrinol. Diabetes 109:S288-S303). GIP acts through binding to specific G-protein coupled GIP receptors located on pancreatic beta-cells (Wheeler, M. B. et al., 1995, Endocrinology 136:4629-4639). Like its sister incretin hormone, glucagon-like peptide-1 (GLP-1), this ability to stimulate insulin secretion plus other potentially beneficial actions on pancreatic beta-cell growth and differentiation have led to much interest in using GIP or GLP-1 receptor agonists in the treatment of type 2 diabetes (Creutzfeldt, W., 2001, Exp. Clin. Endocrinol. Diabetes 109:S288-S303; Holz, G. G. et al., 2003, Curr. Med. Chem. 10:2471-2483).
Since GIP functions as a potent and natural stimulator of insulin secretion released from the intestine by feeding, it is widely expected that antagonists opposing GIP action will block the insulin-releasing actions of GIP and impair both oral glucose tolerance and the glycemic response to nutrient ingestion. In fact, all studies published to date indicate that GIP is a key physiological component of the enteroinsular axis and that functional ablation of GIP leads to impaired glucose homeostasis moving the metabolic characteristic towards a type 2 diabetes phenotype (Gault, V. A. et al., 2002, Biochem. Biophys. Res. Commun. 290:1420-1426).
Dipeptidyl peptidase IV (DPP IV; EC 3.4.14.5) has been identified as a key enzyme responsible for inactivation of GIP and tGLP-1 in serum. This occurs through the rapid removal of the N-terminal dipeptides Tyr1-Ala2 and His7-Ala8 giving rise to the main metabolites GIP(3-42) and GLP-1(9-36)amide, respectively. These truncated peptides are reported to lack biological activity or to even serve as antagonists at GIP or tGLP-1 receptors. The resulting biological half-lives of these incretin hormones in vivo are therefore very short, estimated to be no longer than 5 minutes. DPP IV is completely inhibited in serum by the addition of diprotin A (DPA, 0.1 mmol/l).
In situations of normal glucose regulation and pancreatic B-cell sensitivity, this short duration of action is advantageous in facilitating momentary adjustments to homeostatic control. However, the current goal of a possible therapeutic role of incretin hormones, particularly tGLP-1 in non-insulin dependent diabetes (NIDDM) therapy is frustrated by a number of factors in addition to finding a convenient route of administration. Most notable of these are rapid peptide degradation and rapid absorption (peak concentrations are reached in 20 minutes) and the resulting need for both high dosage and precise timing with meals. Recent therapeutic strategies have focused on precipitated preparations to delay peptide absorption and inhibition of GLP-1 degradation using specific inhibitors of DPP IV. A possible therapeutic role is also suggested by the observation that a specific inhibitor of DPP IV, isoleucine thiazolidide, lowered blood glucose and enhanced insulin secretion in glucose-treated diabetic obese Zucker rats presumably by protecting against catabolism of the incretin hormones tGLP-1 and GIP.
Studies have indicated that tGLP-1 infusion restores pancreatic B-cell sensitivity, insulin secretory oscillations and improved glycemic control in various groups of patients with impaired glucose tolerance (IGT) or NIDDM. Longer term studies also show significant benefits of tGLP-1 injections in NIDDM and possibly IDDM therapy, providing a major incentive to develop an orally effective or long-acting tGLP-1 analogue. Several attempts have been made to produce structurally modified analogues of tGLP-1 which are resistant to DPP IV degradation. A significant extension of serum half-life is observed with His7-glucitol tGLP-1 and tGLP-1 analogues substituted at position 8 with Gly, Aib (amino isobutyric acid), Ser or Thr. However, these structural modifications seem to impair receptor binding and insulinotrophic activity thereby compromising part of the benefits of protection from proteolytic degradation. In recent studies using His7-glucitol tGLP-1, resistance to DPP IV and serum degradation was accompanied by severe loss of insulin releasing activity.
GIP shares not only the same degradation pathway as tGLP-1 but many similar physiological actions, including stimulation of insulin and somatostatin secretion, and the enhancement of glucose disposal. These actions are viewed as key aspects in the antihyperglycemic properties of tGLP-1, and there is therefore good expectation that GIP may have similar potential as NIDDM therapy. Indeed, compensation by GIP is held to explain the modest disturbances of glucose homeostasis observed in tGLP-1 knockout mice. Apart from early studies, the anti-diabetic potential of GIP has not been explored and tGLP-1 may seem more attractive since it is viewed by some as a more potent insulin secretagogue when infused at so called physiological concentrations estimated by radioimmunoassay (RIA).
There is therefore a need for a diabetes treatment that includes an analogue of GIP which can cause release of insulin, yet also be resistant to rapid degradation by DPP IV.